Additional Mosapride to Proton Pump Inhibitor for Gastroesophageal Reflux Disease: A Meta-Analysis.

BACKGROUND AND AIM: In gastroesophageal reflux disease (GERD), the additive effect of mosapride to a proton pump inhibitor (PPI) is still controversial. This meta-analysis integrated randomized controlled trials (RCTs) in which mosapride combined with a PPI was compared with a PPI alone in GERD treatment. METHODS: RCTs were systematically searched with the PubMed, Cochrane library, Web of Science, and the Igaku-Chuo-Zasshi database. We combined the data from the RCTs with a random effects model, calculated the standardized mean difference (SMD) and pooled the risk difference (RD) with 95% confidence intervals (CIs). RESULTS: We included nine RCTs in the present meta-analysis. In the mosapride combined with PPI group, the improvement of the symptom score was significantly greater than that in the PPI alone group without significant heterogeneity (SMD: -0.28, 95% CI: -0.45 to -0.12, p = 0.0007). In the mosapride combined with PPI group, the symptom score after treatment was significantly lower than that in the PPI alone group (SMD: -0.24, 95% CI: -0.42 to -0.06, p = 0.007). CONCLUSIONS: Mosapride combined with a PPI significantly improved the reflux symptom score compared with that of PPI alone.

ß-(1,3)-Glucan derived from Candida albicans induces inflammatory cytokines from macrophages and lamina propria mononuclear cells derived from patients with Crohn's disease.

BACKGROUND/AIMS: Recent research has highlighted the importance of interactions between commensal fungi and intestinal inflammation. However, there are few studies investigating whether commensal fungi contribute to inflammation in patients with Crohn's disease (CD). The aim of this study is to investigate reveal interactions between commensal fungi and host immune cells in CD. METHODS: CD14-positive monocytes were isolated from peripheral blood mononuclear cells from healthy human volunteers and then differentiated in the presence of macrophage colony-stimulating factor (M-CSF) (referred to as M-macrophages, M-Mϕs) or M-CSF and interferon-γ (IFN-γ) (referred to as M-gamma macrophages, Mγ-Mϕs). Cytokine production by these in vitro differentiated macrophages in response to ß-(1,3)-glucan was analyzed by flow cytometry. Expression of Dectin-1 was examined using flow cytometry, western blotting, and quantitative reverse transcription-polymerase chain reaction. Cytokine production by in vitro differentiated macrophages in response to ß-(1,3)-glucan was measured in the presence of an anti-Dectin-1 receptor antagonist, anti-Syr, or an anti-Fas-1 antibody. Cytokine production by lamina propria mononuclear cells (LPMCs) derived from CD patients in response to ß-(1,3)-glucan was also analyzed. RESULTS: Mγ-Mϕs produced a large amount of tumor necrosis factor-α (TNF-α) and interleukin-6 in response to ß-(1,3)-glucan. Dectin-1 expression was significantly higher in Mγ-Mϕs than in M-Mϕs. The increase in TNF-α production by Mγ-Mϕs stimulated with glucan was reversed by blocking Dectin-1, Syr or Fas-1. LPMCs derived from CD patients stimulated with ß-(1,3)-glucan produced significantly higher amount of TNF-α than LPMCs derived from UC patients. CONCLUSIONS: These results suggest that commensal fungal microbiota may contribute to the pathogenesis of CD by inducing macrophages-derived pro-inflammatory cytokines.

Tolvaptan is effective in treating patients with refractory ascites due to cirrhosis.

The treatment of refractory ascites due to cirrhosis is a clinical challenge for hepatologists. Tolvaptan, a novel aquaporin modulator, was made available in Japan in 2013 for the treatment of patients with refractory ascites due to cirrhosis. Despite the potential of this drug, few reports are available regarding its clinical use. The aim of the present study was to clarify the efficacy of tolvaptan in patients with refractory ascites due to cirrhosis and to review the clinical outcomes of treatment. Medical records were retrospectively reviewed for 65 patients with refractory ascites due to cirrhosis who were treated daily with 7.5 mg tolvaptan. The median follow-up time, defined as the period between starting tolvaptan and the last clinic visit or date of mortality, was 175 days (interquartile range 56-406). After one week of tolvaptan treatment, the mean weight reduction was 3.4 kg, with a response rate of 69% (45/65). Subsequently, factors associated with the response to tolvaptan were analyzed. On univariate analysis, maintaining serum sodium (Na) ≥140 mEq/l and an estimated glomerular filtration rate (eGFR) ≥55 ml/min were significant predictors of response (P<0.05). On multivariate analysis, hepatitis C virus etiology, maintaining serum Na ≥140 mEq/l and an eGFR ≥55 ml/min were significant predictors of response (P<0.05). Factors associated with survival were also analyzed using the Cox proportional hazard model. On multivariate analysis, responsiveness to tolvaptan was a predictor of long-term survival (P=0.002), and hyperbilirubinemia was associated with short-term survival (P=0.028). Additionally, Kaplan-Meier analysis with a log-rank test indicated longer survival times in tolvaptan responders than non-responders (P=0.011). In conclusion, tolvaptan was effective in treating patients with refractory ascites due to cirrhosis. In particular, tolvaptan treatment was highly effective for patients with hepatitis C virus etiology and normal serum Na and renal function. Furthermore, response to tolvaptan was associated with longer survival time while hyperbilirubinemia was associated with shorter survival time.

Glycolysis regulates LPS-induced cytokine production in M2 polarized human macrophages.

M1 and M2 macrophages are the key players in innate immunity, and are associated with tissue homeostasis and diseases. Although M2 macrophages are known to depend on fatty acid oxidation (FAO) for their activation, how metabolic pathways affect the production of each cytokine induced by pathogen or bacterial components is unclear. Here, we examined the role of the glycolytic pathway in M2 polarized human macrophages in cytokine production induced by lipopolysaccharide (LPS) stimulation. Human monocytes were isolated from peripheral blood by positive selection for CD14 expression and cultured with macrophage colony-stimulating factor (M-CSF), to obtain M-CSF-induced macrophages (M-MΦ). LPS-induced cytokine production by M-MΦ in the presence or absence of metabolic inhibitors was evaluated. M-MΦ showed a M2 macrophage phenotype with a high IL-10 production level. Glycolytic pathway inhibitors reduced IL-6 production by M-MΦ. Meanwhile, an FAO inhibitor suppressed IL-10 production, while it did not suppress IL-6 production. Interestingly, glycolytic pathway inhibitors downregulated extracellular signal-regulated kinase (ERK) phosphorylation, but FAO inhibitor did not. Nuclear factor kappa B (NF-κB) and the other mitogen-activated protein kinases (MAPKs), p38 and c-jun N-terminal kinase (JNK), were not affected by these metabolic inhibitors. These results suggest that M2 polarized human macrophages use the glycolytic pathway in addition to FAO for cytokine production. Furthermore, ERK may be the key molecule that links metabolic pathways to cytokine production, especially the glycolytic pathway.

Findings of ulceration and severe stricture on MRE can predict prognosis of Crohn's disease in patients treated with anti-TNF treatment.

BACKGROUND: MR enterography (MRE) is useful for evaluating transmural lesions and extra-intestinal complications of Crohn's disease (CD). The aim of this study was to prospectively evaluate whether MRE could detect severe strictures and inflammatory lesions in patients who lost the responsiveness to anti-TNF treatment and whether MRE could predict prognosis of CD patients with clinical remission. PATIENTS AND METHODS: MRE were conducted in 50 patients who were treated with infliximab or adalimumab. The main aims of this study were as follows; (1) to compare the rates of CD lesions of the patients with clinical remission and active disease at the baseline and (2) to assess the MRE findings that were predictors of clinical recurrence among patients with clinical remission at the baseline. RESULTS: The MRE detection rates of markedly increased contrast uptake, severe strictures, and the presence of ulcers were significantly higher in patients with Crohn Disease Activity Index ≥150 than in patients with clinical remission. Over a mean follow-up of 18.2 months, the absence of ulceration (p = 0.001) or severe stricture (p = 0.01) prolonged clinical recurrence among patients with clinical remission at baseline. Expected duration of recurrence significantly prolonged in patients with total magnetic resonance index of activity (MaRIA) <36.3 [29.8 months (95% CI 23.7-35.9)] than in patients with total MaRIA ≥36.3 (13.9 months (95% CI 7.7-20.1). A cut-off value of total MaRIA score of 36.3 had a sensitivity of 75% and specificity of 70% for predicting recurrence. CONCLUSION: Findings of ulceration and severe stricture on MRE predict prognosis of CD patients who were treated with anti-TNF treatment. MRE might be useful for making treatment decisions in patients who lost the effectiveness of medical treatments.

Glycolytic pathway affects differentiation of human monocytes to regulatory macrophages.

Cellular metabolic state and individual metabolites have been reported to regulate the functional phenotype of immune cells. Cytokine production by regulatory and inflammatory macrophages is thought to mainly involve fatty acid oxidation and glycolysis, respectively, which fuel mitochondrial oxidative phosphorylation. However, the association between metabolic pathways and the acquisition of specific macrophage phenotypes remains unclear. This study assessed the relationship between glycolysis and the differentiation of regulatory macrophages. Human monocytes derived from peripheral blood were cultured in vitro in the presence of macrophage colony-stimulating factor to yield regulatory macrophages (M-Mϕs). M-Mϕs had a regulatory macrophage phenotype and produced substantial IL-10 following stimulation with lipopolysaccharide. To analyze the role of glycolysis, glycolysis inhibitors (2-deoxy-d-glucose or dichloroacetate) were added during M-Mϕ differentiation. These cells cultured with glycolysis inhibitors produced significantly lower amounts of IL-10, but produced significantly higher amounts of IL-6 compared to M-Mϕs differentiated without glycolysis inhibitors. Such phenotypic change of M-Mϕs differentiated with glycolysis inhibitors was associated with the alteration of the gene expression pattern related to macrophage differentiation, such as CSF1, MMP9 and VEGFA. M-Mϕs differentiated with glycolysis inhibitors seemed to retain plasticity to become IL-10 producing cells. Furthermore, increased level of pyruvate in culture medium was found to partially reverse the effects of glycolysis inhibitors on cytokine production of M-Mϕs. These results indicate the importance of glycolytic pathway in macrophage differentiation to a regulatory phenotype, and pyruvate may be one of the key metabolites in this process.

The Ulcerative Colitis Endoscopic Index of Severity is Useful to Predict Medium- to Long-Term Prognosis in Ulcerative Colitis Patients with Clinical Remission.

BACKGROUND: The ulcerative colitis endoscopic index of severity [UCEIS] is a validated scoring system. Nevertheless, few studies have investigated its usefulness in clinical settings. In this study, we aimed to predict the clinical prognosis of patients with ulcerative colitis [UC] in clinical remission using the UCEIS. METHODS: A total of 285 UC patients who underwent a colonoscopy between April 2012 and March 2013 were enrolled. We reviewed clinical characteristics and endoscopic scores at the time of the colonoscopy and checked the clinical remission rate of the patients until September 2015. Clinical remission and recurrence were defined as a partial Mayo score of ≤1 and ≥3, respectively. RESULTS: UCEIS was strongly correlated with the Mayo endoscopic score [r=0.93], moderately correlated with clinical severity [r=0.64] and mildly correlated with C-reactive protein [r=0.34]. The recurrence rate increased gradually as it became more endoscopically severe [5.0% for UCEIS=0, 22.4% for UCEIS=1, 27.0% for UCEIS=2, 35.7% for UCEIS=3 and 75.0% for UCEIS=4-5] in patients with clinical remission. UCEIS and the concomitant use of thiopurine were independent factors predicting clinical recurrence. A multivariate analysis indicated that the absence of bleeding [p≤0.001] and the absence of mucosal damage [p<0.001] in a colonoscopy were independent factors for prolongation of clinical remission. CONCLUSION: The UCEIS is useful to predict the medium- to long-term outcomes of UC patients with clinical remission. The absence of bleeding or mucosal damage is important for maintaining clinical remission.

Clinical Efficacy and Safety of Oral Qing-Dai in Patients with Ulcerative Colitis: A Single-Center Open-Label Prospective Study.

BACKGROUND/AIMS: Chinese herbal medicine Qing-Dai (also known as indigo naturalis) has been used to treat various inflammatory conditions. However, not much has been studied about the use of oral Qing-Dai in the treatment for ulcerative colitis (UC) patients. Studies exploring alternative treatments for UC are of considerable interest. In this study, we aimed at prospectively evaluating the safety and efficacy of Qing-Dai for UC patients. METHODS: The open-label, prospective pilot study was conducted at Keio University Hospital. A total of 20 patients with moderate UC activity were enrolled. Oral Qing-Dai in capsule form was taken twice a day (daily dose, 2 g) for 8 weeks. RESULTS: At week 8, the rates of clinical response, clinical remission, and mucosal healing were 72, 33, and 61%, respectively. The clinical and endoscopic scores, CRP levels, and fecal occult blood results were also significantly improved. We observed 2 patients with mild liver dysfunction; 1 patient discontinued due to infectious colitis and 1 patient discontinued due to mild nausea. CONCLUSION: This is the first prospective study indicating that oral Qing-Dai is effective for inducing remission in patients with moderate UC activity and can be tolerated. Thus, Qing-Dai may be considered an alternative treatment for patients, although further investigation is warranted.

Ulcerative colitis endoscopic index of severity is associated with long-term prognosis in ulcerative colitis patients treated with infliximab.

BACKGROUND AND AIM: Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is characterized by periods of remission and episodes of relapse. Mucosal healing is an emerging therapeutic target in UC and various scoring systems have been used. The UC endoscopic index of severity (UCEIS) is the only validated endoscopic index at present, with minimum interobserver variation. Correlation of UCEIS scores after treatment and clinical outcomes of UC has not been examined. In the present study, we aimed to evaluate the usefulness of UCEIS after treatment with infliximab. METHODS: The medical records of 82 UC patients, treated with infliximab at Keio University Hospital between October 2010 and July 2013, were reviewed retrospectively. Endoscopic findings were evaluated based on the UCEIS. RESULTS: Mean pre-therapeutic UCEIS score was 5.1. Pre-therapeutic UCEIS scores were not associated with short-term outcomes. Forty-five patients underwent colonoscopy at 3-12 months after starting treatment; mean post-therapeutic UCEIS score was 2.4, with a score of 0-1 in 16 (35.6%) patients, 2-4 in 19 (42.2%) patients, and 5-8 in 10 (22.2%) patients. Importantly, a post-therapeutic UCEIS score of 0 or 1 after treatment was associated with a favorable long-term outcome. CONCLUSION: UCEIS score is a useful instrument for evaluating endoscopic improvement in UC patients treated with infliximab, and mucosal healing may be defined with a UCEIS score of 0 or 1.

Endoscopic Severity Predicts Long-Term Prognosis in Crohn's Disease Patients with Clinical Remission.

INTRODUCTION: Mucosal healing has emerged as a desirable treatment goal in clinical practice for patients with Crohn's disease (CD). The aim of this study was to assess the relationship between endoscopic activity and the long-term prognosis of CD using simple endoscopic score for Crohn's disease (SESCD) and Rutgeerts' score. METHODS: We conducted a cohort study in clinical practice at a single center. Among CD patients who underwent colonoscopy between July 2008 and June 2011 at our hospital, 131 patients with clinical remission were selected, and the patients were divided into 2 groups: a non-surgical group (n = 84) and a surgical group (n = 47). The primary endpoint of this study was to assess the associations between variables and clinical relapse after endoscopic procedures. The cut-off levels of SESCD or Rutgeerts' score for the prediction of relapse were also assessed in patients with clinical remission. RESULTS: In the non-surgical group, SESCD and C-reactive protein at baseline were significantly higher in patients who had clinical recurrence than in patients who maintained remission. A factor of SESCD ≤2 was independently associated with sustained remission, even in patients with clinical remission. In the surgical group, patients with Rutgeerts' scores ≤1 had significantly prolonged clinical remission compared to patients with Rutgeerts' scores ≥3. CONCLUSION: A cut-off value of SESCD ≤2 and a Rutgeerts' score ≤1 enabled the prediction of long-term prognosis. These cut-off values could be used in clinical trials of endoscopic remission from the point of view of the clinical outcomes of CD.

Early intervention with adalimumab may contribute to favorable clinical efficacy in patients with Crohn's disease.

BACKGROUND: We evaluated the clinical efficacy of adalimumab (ADA) for Crohn's disease (CD) and analyzed predictive factors for clinical remission and long-term prognosis. METHODS: We retrospectively reviewed the medical records of 45 patients treated with ADA for CD at Keio University Hospital between October 2010 and March 2014. Clinical remission was defined as a Harvey-Bradshaw index of ≤4. RESULTS: Twenty-eight of 45 patients (62.2%) achieved clinical remission at week 4. Among these 28 patients, 18 patients (64.3%) maintained clinical remission at week 26, and among these, 16 patients (88.9%) maintained clinical remission at week 52. Absence of a history of bowel resection and absence of prior anti-tumor necrosis factor (anti-TNF) therapy were significant predictive factors for clinical remission at week 4 upon multivariate logistic regression analyses. Younger age and a disease duration of ≤3 years correlated with clinical remission at week 26 upon univariate analyses. Patients without a history of bowel resection showed significantly better long-term prognosis than those with a history of bowel resection (p = 0.01). None of the patients contracted a serious infectious disease. CONCLUSIONS: Younger age, shorter duration of disease, being naive to anti-TNF antagonists, and absence of a history of bowel resection were associated with the efficacy of ADA in CD patients.